US5364644A - Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders - Google Patents
Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders Download PDFInfo
- Publication number
- US5364644A US5364644A US08/012,145 US1214593A US5364644A US 5364644 A US5364644 A US 5364644A US 1214593 A US1214593 A US 1214593A US 5364644 A US5364644 A US 5364644A
- Authority
- US
- United States
- Prior art keywords
- sup
- glucarate
- calcium
- vitamin
- sub
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 208000035150 Hypercholesterolemia Diseases 0.000 title claims abstract description 29
- 230000001413 cellular effect Effects 0.000 title abstract description 28
- 230000002265 prevention Effects 0.000 title abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 25
- 230000003463 hyperproliferative effect Effects 0.000 title description 7
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 241001465754 Metazoa Species 0.000 claims abstract description 20
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 41
- 239000011707 mineral Substances 0.000 claims description 40
- 235000010755 mineral Nutrition 0.000 claims description 38
- 229940088594 vitamin Drugs 0.000 claims description 29
- 239000011782 vitamin Substances 0.000 claims description 29
- 229930003231 vitamin Natural products 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 22
- 235000013343 vitamin Nutrition 0.000 claims description 22
- UGZVNIRNPPEDHM-SBBOJQDXSA-L calcium;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioate Chemical compound [Ca+2].[O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O UGZVNIRNPPEDHM-SBBOJQDXSA-L 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 14
- UBYZGUWQNIEQMH-SBBOJQDXSA-M potassium;(2s,3s,4s,5r)-2,3,4,5,6-pentahydroxy-6-oxohexanoate Chemical compound [K+].OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O UBYZGUWQNIEQMH-SBBOJQDXSA-M 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 10
- 241000282414 Homo sapiens Species 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 9
- 239000007894 caplet Substances 0.000 claims description 6
- 238000013268 sustained release Methods 0.000 claims description 6
- 239000012730 sustained-release form Substances 0.000 claims description 6
- 239000011785 micronutrient Substances 0.000 claims description 3
- 235000013369 micronutrients Nutrition 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 206010014476 Elevated cholesterol Diseases 0.000 claims 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 abstract description 40
- 239000003795 chemical substances by application Substances 0.000 abstract description 14
- 230000001225 therapeutic effect Effects 0.000 abstract description 9
- 235000005911 diet Nutrition 0.000 description 67
- DSLZVSRJTYRBFB-LLEIAEIESA-L D-glucarate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O DSLZVSRJTYRBFB-LLEIAEIESA-L 0.000 description 66
- 230000037213 diet Effects 0.000 description 50
- 239000011575 calcium Substances 0.000 description 31
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 30
- 229960005069 calcium Drugs 0.000 description 30
- 229910052791 calcium Inorganic materials 0.000 description 30
- 241000700159 Rattus Species 0.000 description 19
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 19
- 230000000378 dietary effect Effects 0.000 description 17
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- 235000012000 cholesterol Nutrition 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 14
- 239000011574 phosphorus Substances 0.000 description 14
- 229910052698 phosphorus Inorganic materials 0.000 description 14
- 150000003722 vitamin derivatives Chemical class 0.000 description 14
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 229960003512 nicotinic acid Drugs 0.000 description 13
- 235000001968 nicotinic acid Nutrition 0.000 description 13
- 239000011664 nicotinic acid Substances 0.000 description 13
- 230000001028 anti-proliverative effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 11
- 239000003529 anticholesteremic agent Substances 0.000 description 11
- 210000001072 colon Anatomy 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 10
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 10
- 229930003316 Vitamin D Natural products 0.000 description 10
- 239000011777 magnesium Substances 0.000 description 10
- 229910052749 magnesium Inorganic materials 0.000 description 10
- 229940091250 magnesium supplement Drugs 0.000 description 10
- 230000002062 proliferating effect Effects 0.000 description 10
- 235000019166 vitamin D Nutrition 0.000 description 10
- 239000011710 vitamin D Substances 0.000 description 10
- 150000003710 vitamin D derivatives Chemical class 0.000 description 10
- 229940046008 vitamin d Drugs 0.000 description 10
- 238000008214 LDL Cholesterol Methods 0.000 description 9
- 108010007622 LDL Lipoproteins Proteins 0.000 description 9
- 102000007330 LDL Lipoproteins Human genes 0.000 description 9
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 9
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 9
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 9
- 108010069201 VLDL Cholesterol Proteins 0.000 description 9
- 229930003270 Vitamin B Natural products 0.000 description 9
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 9
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 9
- 239000011591 potassium Substances 0.000 description 9
- 229960003975 potassium Drugs 0.000 description 9
- 229910052700 potassium Inorganic materials 0.000 description 9
- 235000019156 vitamin B Nutrition 0.000 description 9
- 239000011720 vitamin B Substances 0.000 description 9
- 235000005282 vitamin D3 Nutrition 0.000 description 9
- 239000011647 vitamin D3 Substances 0.000 description 9
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 9
- 229940021056 vitamin d3 Drugs 0.000 description 9
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 8
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- 229940095625 calcium glucarate Drugs 0.000 description 8
- 239000003925 fat Substances 0.000 description 8
- 235000019197 fats Nutrition 0.000 description 8
- 235000009200 high fat diet Nutrition 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- 235000016709 nutrition Nutrition 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 238000002372 labelling Methods 0.000 description 7
- 239000000395 magnesium oxide Substances 0.000 description 7
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 6
- 229910052770 Uranium Inorganic materials 0.000 description 6
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 6
- -1 fish Chemical compound 0.000 description 6
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
- 208000019622 heart disease Diseases 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 229960003471 retinol Drugs 0.000 description 6
- 235000020944 retinol Nutrition 0.000 description 6
- 239000011607 retinol Substances 0.000 description 6
- 208000017520 skin disease Diseases 0.000 description 6
- 150000003626 triacylglycerols Chemical class 0.000 description 6
- 208000005623 Carcinogenesis Diseases 0.000 description 5
- 108010010234 HDL Lipoproteins Proteins 0.000 description 5
- 102000015779 HDL Lipoproteins Human genes 0.000 description 5
- 241000282412 Homo Species 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 230000036952 cancer formation Effects 0.000 description 5
- 231100000504 carcinogenesis Toxicity 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 235000019152 folic acid Nutrition 0.000 description 5
- 239000011724 folic acid Substances 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 235000014105 formulated food Nutrition 0.000 description 5
- 230000000871 hypocholesterolemic effect Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 229910052742 iron Inorganic materials 0.000 description 5
- 229910052748 manganese Inorganic materials 0.000 description 5
- 239000011572 manganese Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 210000002966 serum Anatomy 0.000 description 5
- 210000000813 small intestine Anatomy 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 235000019157 thiamine Nutrition 0.000 description 5
- 239000011721 thiamine Substances 0.000 description 5
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 5
- 235000012431 wafers Nutrition 0.000 description 5
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 4
- 229920001268 Cholestyramine Polymers 0.000 description 4
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 4
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 4
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 4
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 108010062497 VLDL Lipoproteins Proteins 0.000 description 4
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 4
- 229930003268 Vitamin C Natural products 0.000 description 4
- 229930003427 Vitamin E Natural products 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229960004494 calcium gluconate Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 235000014633 carbohydrates Nutrition 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 229940014144 folate Drugs 0.000 description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 230000035764 nutrition Effects 0.000 description 4
- 235000019161 pantothenic acid Nutrition 0.000 description 4
- 239000011713 pantothenic acid Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 235000019192 riboflavin Nutrition 0.000 description 4
- 229960002477 riboflavin Drugs 0.000 description 4
- 239000002151 riboflavin Substances 0.000 description 4
- 239000011669 selenium Substances 0.000 description 4
- 229910052711 selenium Inorganic materials 0.000 description 4
- 229940091258 selenium supplement Drugs 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000013223 sprague-dawley female rat Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 235000019155 vitamin A Nutrition 0.000 description 4
- 239000011719 vitamin A Substances 0.000 description 4
- 235000019154 vitamin C Nutrition 0.000 description 4
- 239000011718 vitamin C Substances 0.000 description 4
- 235000019165 vitamin E Nutrition 0.000 description 4
- 229940046009 vitamin E Drugs 0.000 description 4
- 239000011709 vitamin E Substances 0.000 description 4
- 229940045997 vitamin a Drugs 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000007766 Kaposi sarcoma Diseases 0.000 description 3
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 3
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 229930003448 Vitamin K Natural products 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 229960002685 biotin Drugs 0.000 description 3
- 235000020958 biotin Nutrition 0.000 description 3
- 239000011616 biotin Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000004227 calcium gluconate Substances 0.000 description 3
- 235000013927 calcium gluconate Nutrition 0.000 description 3
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 3
- 150000001746 carotenes Chemical class 0.000 description 3
- 235000005473 carotenes Nutrition 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 229910052804 chromium Inorganic materials 0.000 description 3
- 239000011651 chromium Substances 0.000 description 3
- 230000000112 colonic effect Effects 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 3
- 210000005075 mammary gland Anatomy 0.000 description 3
- 229940029985 mineral supplement Drugs 0.000 description 3
- 235000020786 mineral supplement Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- BDRTVPCFKSUHCJ-UHFFFAOYSA-N molecular hydrogen;potassium Chemical compound [K].[H][H] BDRTVPCFKSUHCJ-UHFFFAOYSA-N 0.000 description 3
- 229910052750 molybdenum Inorganic materials 0.000 description 3
- 239000011733 molybdenum Substances 0.000 description 3
- 229940055726 pantothenic acid Drugs 0.000 description 3
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229930003799 tocopherol Natural products 0.000 description 3
- 229960001295 tocopherol Drugs 0.000 description 3
- 239000011732 tocopherol Substances 0.000 description 3
- 235000010384 tocopherol Nutrition 0.000 description 3
- 239000011573 trace mineral Substances 0.000 description 3
- 235000013619 trace mineral Nutrition 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- 235000019168 vitamin K Nutrition 0.000 description 3
- 239000011712 vitamin K Substances 0.000 description 3
- 150000003721 vitamin K derivatives Chemical class 0.000 description 3
- 229940046010 vitamin k Drugs 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- XVYGMAIZBNNQTF-QRIOHSITSA-N (2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioic acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O XVYGMAIZBNNQTF-QRIOHSITSA-N 0.000 description 2
- HTBIAUMDQYXOFG-UHFFFAOYSA-N 3-methyl-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]pentanoic acid Chemical compound CCC(C)C(C(O)=O)N(C)C(=O)OC(C)(C)C HTBIAUMDQYXOFG-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- DGAKHGXRMXWHBX-ONEGZZNKSA-N Azoxymethane Chemical compound C\N=[N+](/C)[O-] DGAKHGXRMXWHBX-ONEGZZNKSA-N 0.000 description 2
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 102100030797 Conserved oligomeric Golgi complex subunit 2 Human genes 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- 101000920113 Homo sapiens Conserved oligomeric Golgi complex subunit 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
- 201000008754 Tenosynovial giant cell tumor Diseases 0.000 description 2
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- RSYUFYQTACJFML-DZGCQCFKSA-N afzelechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C=C1 RSYUFYQTACJFML-DZGCQCFKSA-N 0.000 description 2
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 2
- 235000021152 breakfast Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000003183 carcinogenic agent Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 235000020940 control diet Nutrition 0.000 description 2
- 229940116318 copper carbonate Drugs 0.000 description 2
- 229910000009 copper(II) carbonate Inorganic materials 0.000 description 2
- GEZOTWYUIKXWOA-UHFFFAOYSA-L copper;carbonate Chemical compound [Cu+2].[O-]C([O-])=O GEZOTWYUIKXWOA-UHFFFAOYSA-L 0.000 description 2
- 239000002285 corn oil Substances 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 239000011646 cupric carbonate Substances 0.000 description 2
- 235000019854 cupric carbonate Nutrition 0.000 description 2
- 230000002548 cytokinetic effect Effects 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 235000020805 dietary restrictions Nutrition 0.000 description 2
- 208000035647 diffuse type tenosynovial giant cell tumor Diseases 0.000 description 2
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical compound [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 210000000981 epithelium Anatomy 0.000 description 2
- 229960002413 ferric citrate Drugs 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 235000012631 food intake Nutrition 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000000260 hypercholesteremic effect Effects 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 210000004698 lymphocyte Anatomy 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 231100000957 no side effect Toxicity 0.000 description 2
- 208000007420 pigmented villonodular synovitis Diseases 0.000 description 2
- JLKDVMWYMMLWTI-UHFFFAOYSA-M potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 description 2
- 239000001230 potassium iodate Substances 0.000 description 2
- 235000006666 potassium iodate Nutrition 0.000 description 2
- 229940093930 potassium iodate Drugs 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 2
- 229910052939 potassium sulfate Inorganic materials 0.000 description 2
- 235000011151 potassium sulphates Nutrition 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 230000002207 retinal effect Effects 0.000 description 2
- 235000021003 saturated fats Nutrition 0.000 description 2
- 239000011781 sodium selenite Substances 0.000 description 2
- 235000015921 sodium selenite Nutrition 0.000 description 2
- 229960001471 sodium selenite Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 150000004685 tetrahydrates Chemical class 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 235000013311 vegetables Nutrition 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 235000019195 vitamin supplement Nutrition 0.000 description 2
- 239000011667 zinc carbonate Substances 0.000 description 2
- 235000004416 zinc carbonate Nutrition 0.000 description 2
- 229910000010 zinc carbonate Inorganic materials 0.000 description 2
- YKSVGLFNJPQDJE-YDMQLZBCSA-N (19E,21E,23E,25E,27E,29E,31E)-33-[(2R,3S,4R,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-17-[7-(4-aminophenyl)-5-hydroxy-4-methyl-7-oxoheptan-2-yl]-1,3,5,7,37-pentahydroxy-18-methyl-9,13,15-trioxo-16,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid Chemical compound CC(CC(C)C1OC(=O)CC(=O)CCCC(=O)CC(O)CC(O)CC(O)CC2(O)CC(O)C(C(CC(O[C@@H]3O[C@H](C)[C@@H](O)[C@@H](N)[C@@H]3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\C1C)O2)C(O)=O)C(O)CC(=O)C1=CC=C(N)C=C1 YKSVGLFNJPQDJE-YDMQLZBCSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 235000000638 D-biotin Nutrition 0.000 description 1
- 239000011665 D-biotin Substances 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000014121 butter Nutrition 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- GUPPESBEIQALOS-ZVGUSBNCSA-L calcium;(2r,3r)-2,3-dihydroxybutanedioate Chemical compound [Ca+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O GUPPESBEIQALOS-ZVGUSBNCSA-L 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229960004348 candicidin Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000010001 cellular homeostasis Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000004736 colon carcinogenesis Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 235000014541 cooking fats Nutrition 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001767 dextrothyroxine Drugs 0.000 description 1
- 235000013325 dietary fiber Nutrition 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 235000013601 eggs Nutrition 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 229940037395 electrolytes Drugs 0.000 description 1
- 235000020882 elemental diet Nutrition 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 235000021112 essential micronutrients Nutrition 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 235000015203 fruit juice Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000013310 margarine Nutrition 0.000 description 1
- 239000003264 margarine Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229960004051 menadione sodium bisulfite Drugs 0.000 description 1
- XDPFHGWVCTXHDX-UHFFFAOYSA-M menadione sodium sulfonate Chemical compound [Na+].C1=CC=C2C(=O)C(C)(S([O-])(=O)=O)CC(=O)C2=C1 XDPFHGWVCTXHDX-UHFFFAOYSA-M 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 239000002366 mineral element Substances 0.000 description 1
- 235000020772 multivitamin supplement Nutrition 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 229940108325 retinyl palmitate Drugs 0.000 description 1
- 235000019172 retinyl palmitate Nutrition 0.000 description 1
- 239000011769 retinyl palmitate Substances 0.000 description 1
- 229940088153 riboflavin 1.8 mg Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940042585 tocopherol acetate Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000036325 urinary excretion Effects 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 235000008939 whole milk Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/035—Organic compounds containing oxygen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/15—Vitamins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Definitions
- Hypercholesterolemia and cellular hyperproliferative disorders are causative factors in several different pathologies, many of which cause death.
- hypercholesterolemia also including hyperlipidemia for purposes of the present invention, is a contributing factor in the development of heart disease and stroke.
- Heart disease is the single biggest cause of death in the United States.
- Cellular hyperproliferative disorders include such diseases as psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma; chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, proliferative diseases of retinal cells, and some cancers. Although several of the cellular proliferative disorders only cause discomfort and patient suffering, several, such as cancer, may be fatal. In the United States alone, tens of thousands of people die from cancer each year, and additional tens of thousands suffer from the numerous other cellular hyperproliferative disorders.
- Arteriosclerosis is a major factor in the development of heart disease and stroke.
- various dietary components such as, lipids, proteins, carbohydrates, dietary fibers, and trace metals, have been investigated. It is commonly assumed that plethoric diets high in fats and cholesterol are a major cause in the development of hypercholesterolemia.
- plethoric diets are known to be associated with increased levels of low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) (1,2).
- LDL low density lipoproteins
- VLDL very low density lipoproteins
- HDL high density lipoproteins
- Serum cholesterol levels that are generally accepted as within normal ranges in the United States are higher than those found among comparable individuals in populations with a low incidence of arteriosclerosis.
- the optimal serum cholesterol for a middle-aged American man is probably about 200 mg/100 ml, or less.
- hypercholesterolemia is generally defined as any value above the 95th percentile for the population, which in Americans ranges from about 230 mg/100 ml in individuals less than 20 years old, to about 300 mg/100 ml in individuals greater than 60 years old. These limits are, however, probably excessive because of the known risk of cholesterol values at these levels.
- practicing physicians frequently use a convenient rule of thumb which holds that any level of serum cholesterol greater than about 200 mg/100 ml plus the person's age should be considered abnormal. Even these limits may be too high.
- diet modification e.g., the strict avoidance of the sources of cholesterol and saturated fats.
- the patient is instructed to avoid meat, especially organ meats and obviously fat, egg, whole milk, cream, butter, lard, and saturated cooking fats.
- These foods are replaced in the patient's diet with foods low in saturated fat and cholesterol, e.g., fish, vegetables, poultry, polyunsaturated oils, and margarine.
- saturated fat and cholesterol e.g., fish, vegetables, poultry, polyunsaturated oils, and margarine.
- this therapy requires a dramatic lifestyle change and the substituted foods are generally less flavorful, patient compliance is very poor.
- cholestyramine a bile acid sequestrant
- a dosage of about 16 to about 32 grams in 2 to 4 divided daily doses will, for example, lower LDL levels by 25 to 50%, probably by increasing LDL removal.
- cholestyramine is associated with side effects, such as constipation and poor taste that limit general patient acceptance.
- cholestyramine and another hypocholesterolemic drug, candicidin apparently increased azoxymethanol-induced bowel tumorigenesis in the rat (3,4).
- niacin is useful in hypercholesterolemia, but the high dosage required, three to nine grams per day in divided dosage with meals, coupled with the side effects of gastric irritability, hyperuricemia, hyperglycemia, flushing and pruritus, prevents its general use. Niacin is most effective when combined with cholestyramine.
- Thyroid analogs e.g., D-thyroxine
- Thyroid analogs effectively lower LDL levels, but are contraindicated in patients with suspected or proven heart disease. Further, since these agents mimic thyroid hormone, they produce a plethora of untoward effects in the body. Accordingly, these agents have no little or no place in the therapy of the typical hypercholesterolemia patient. Other agents which are presently utilized are generally less effective than strict dietary management.
- Heart disease kills tens of thousands of Americans every year.
- the major cause of heart disease is the accumulation of plaque in the coronary arteries. This accumulation is presumably cause by excessively high levels of serum cholesterol.
- hypocholesterolemic agent commercially available that has found wide patient acceptance.
- hypocholesterolemic agent which effectively lowers serum cholesterol in a human without the attending side effects typically associated with previous hypocholesterolemic agents. Further, it would be advantageous to provide a hypocholesterolemic agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing a hypocholesterolemic agent which is administered multiple times or once daily, particularly if a slow release formulation is used. It would also be advantageous to provide a hypocholesterolemic agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against hypercholesterolemia. A still further advantage would be realized in providing a hypocholesterolemic agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against hypercholesterolemia.
- Cellular hyperproliferative disorders are generally characterized by the hyperproliferation and incomplete differentiation of cells. For example, in psoriasis vulgaris there is a hyperproliferation of incompletely differentiated cells of the epidermis. Presently, it is not fully understood what causes certain cells to reproduce rapidly when the host has no apparent need for them. Since growing evidence suggests that cellular hyperproliferation is involved with chemically induced carcinogenesis, the inhibition of cellular proliferation may also be an effective tool for prevention of certain cancers.
- the inhibition of cellular proliferation may be an effective tool for preventing psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several other diseases associated with the hyperproliferation of cells such as chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, or hairy cell leukemia, or proliferative diseases of retinal cells, for example.
- diseases associated with the hyperproliferation of cells such as chronic adult respiratory syndrome, large granular lymphocyte/natural killer cell proliferative disease, haemopoietic proliferative disorders, B-cell proliferative disorders, pigmented villonodular synovitis, or hairy cell leukemia, or proliferative diseases of retinal cells, for example.
- an antiproliferation agent which effectively inhibits cellular hyperproliferation in a human
- an antiproliferative agent which is effective when administered to a patient in need thereof in a relatively small dose. Another and important advantage is realized by providing an antiproliferative agent which may be administered once daily. It would also be advantageous to provide an antiproliferative agent which is incorporated into a vehicle, such as a multivitamin and mineral tablet, and administered daily to the general population to prophylactically protect the population against cellular hyperproliferation. A still further advantage would be realized in providing an antiproliferative agent which is safely, and inexpensively added to foodstuffs intended for consumption by the general population, and thereby provide prophylactic protection against the disease typically associated the with hyperproliferation of cells.
- One aspect of the invention is directed to a method for the prevention and treatment of hypercholesterolemia.
- a further aspect of the present invention is directed to a method for the prevention and treatment of cellular hyperproliferation.
- an animal is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
- the animal is preferably a human.
- the pharmaceutical formulation may be a tablet, capsule, suspension, or solution.
- the pharmaceutical formulation may be administered by mouth or by injection.
- the pharmaceutically acceptable salt is preferably selected from the groups consisting of calcium glucarate, sodium glucarate, potassium hydrogen glucarate, and magnesium glucarate.
- a human is administered daily a sustained release pharmaceutical formulation including from about 200 mg to about 8,000 mg of glucaric acid or a pharmaceutical acceptable salt thereof.
- the pharmaceutical formulation also includes a multiplicity of vitamins, minerals and micronutrients. The preparation is intended as prophylactic protection against the onset of hypercholesterolemia and cellular hyperproliferation.
- a method for the prevention of hypercholesterolemia and/or cellular hyperproliferation in a population of humans and animals.
- the method provides for adding to a selected foodstuff a predetermined amount of glucaric acid or a pharmaceutical acceptable salt thereof, and thereafter, providing a sufficient quantity of the foodstuff to the population of humans and animals such that the humans and animals ingest a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
- the present invention provides a formula and method for the treatment of hypercholesterolemia and cellular hyperproliferation. More specifically, the present invention provides a method for administering a formula including glucaric acid or a pharmaceutically acceptable salt thereof for the prevention and treatment of hypercholesterolemia and cellular hyperproliferation in humans and animals. It has been determined that glucaric acid, and the pharmaceutically acceptable salts thereof, significantly lower the total level of serum cholesterol and LDL in animals when administered in therapeutic amounts while simultaneously inhibiting cellular hyperproliferation. It is intended that glucaric acid or a pharmaceutically acceptable salt thereof is employed alone or in combination with other medicinal agents for the prevention and treatment of hypercholesterolemia and/or cellular hyperproliferation.
- D-Glucaric acid is a six-carbon, straight-chain dicarboxylic acid and is sometimes referred to as D-saccharic acid. Chemically, a schematic formula for D-glucaric acid is COOH--(CHOH) 4 --COOH.
- the salts of D-glucaric acid (glucaric acid) are referred to as D-glucarates (glucarates), e.q., calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate.
- Glucaric acid and the salts thereof are normal metabolic products in mammals.
- glucuronic acid was found to be enzymatically oxidized to glucaric acid.
- Glucaric acid is the sole end product of the glucuronic acid pathway in guinea pigs and primates (7).
- Significant interindividual differences have been reported (8) in normal healthy populations. It was observed (9) that the urinary excretion of glucaric acid in cancer patients and tumor-bearing rats was significantly lower than in healthy controls.
- uninvolved liver tissue was found to have a lowered glucaric acid level (7). Further, studies have shown that cancerous tissues lack the glucaric acid-synthesizing system (7).
- glucaric acid/glucarate The physiological function of glucaric acid/glucarate remains unclear, although it appears to be an important carbohydrate for cell viability and homeostasis. It is not known if glucaric acid is an essential nutrient for normal subjects. Some plants have been analyzed as identifiable sources rich in glucaric acid (10, 11). Recently glucaric acid/glucarate have been found in cruciferous vegetables (12). Glucaric acid/glucarate content is high in young seedlings and sprouts but low in respective seeds (13). Glucaric acid/glucarates are generally non-toxic, and no adverse effects have been observed from prolonged feeding of potassium hydrogen glucarate to rats (14, 15) or calcium glucarate to rats (16) and mice (17).
- a medicament including therapeutic amounts of glucaric acid or a pharmaceutically acceptable salt thereof useful in the treatment and prevention of hypercholesterolemia cellular and hyperproliferation.
- glucaric acid or a pharmaceutically acceptable salt thereof useful in the treatment and prevention of hypercholesterolemia cellular and hyperproliferation.
- the present inventors have determined that, by administering therapeutic amounts of glucaric acid/glucarate, total serum cholesterol could be significantly reduced. Studies with this compound demonstrated that HDL, LDL, and VLDL were reduced and, most significantly, serum LDL was reduced. Further, studies have shown that glucarates are generally non-toxic and cause little or no side effects in the individual being treated.
- glucaric acid inhibits cellular hyperproliferation in animals. Since cellular hyperproliferation is related not only to the development of certain cancers but also other diseases, e.g., psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several proliferative disorders, it is believed that the use of glucarates for this purpose would be a significant departure from prior method of preventing or treating diseases associated with cellular hyperproliferation.
- diseases e.g., psoriasis vulgaris, dysplastic skin diseases, pigmentary skin diseases, Kaposi's sarcoma and several proliferative disorders
- a method wherein an individual in need thereof is administered a pharmaceutical formulation including a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
- the inventive method is intended to reduce cholesterol in those individuals suffering from hypercholesterolemia and to inhibit cellular hyperproliferation in those individuals in need thereof. Further the formulation and method is intended to prevent the onset of hypercholesterolemia and/or cellular hyperproliferation in those individuals at risk of developing it.
- the present inventors have demonstrated that glucarates significantly lower total serum cholesterol in rats, and it is believed that this therapeutic effect will also be observed in humans. Moveover, the present inventors have also demonstrated that glucarates inhibit cellular proliferation. It is intended that this discovery be applied beneficially to treat those individuals suffering from cellular hyperproliferation disorders.
- Glucaric acid or glucarates may be compounded in numerous acceptable pharmaceutical formulations.
- Preferable pharmaceutical formulations include tablets, capsules, insuflations, syrups, suspensions, solutions, suppositories, injections, and any sustained release preparation thereof. More preferable, the compound is incorporated into a sustained release tablet or capsule which will provide a hypocholesterolemic and antiproliferative therapeutic effect for the longest possible duration. Thus, the individual receives the maximum benefit from the compound, and patient compliance is increased because the dosage form is administered daily.
- Injections which are useful in the practice of the present invention include intravascular (e.g., intravenous or intraarterial) subcutaneous, intramuscular, intralymphatic, intraperitoneal, and intrapleural. The most preferable route of the administration for an injection is, however, intravenous.
- the pharmaceutical formulation administered to the individual in need thereof preferably includes a therapeutically effective amount of glucaric acid or a pharmaceutically acceptable salt thereof.
- the individual is administered daily from about 10 mg to about 16,000 mg of glucaric acid or a pharmaceutically acceptable salt thereof per day compounded as a single or divided dose. More preferably the individual is administered from about 200 mg to about 8,000 mg per day.
- the preferred pharmaceutically acceptable salt of glucaric acid includes any salt of glucaric acid which is both non-toxic and does not substantially diminish the therapeutic effect of the compound.
- preferred pharmaceutically acceptable salts of glucaric acid include calcium glucarate, sodium glucarate, magnesium glucarate, and potassium hydrogen glucarate. More preferably, however, the pharmaceutical formulation includes potassium hydrogen glucarate and/or calcium glucarate.
- glucaric acid and/or glucarate is incorporated as a hypocholesterolemic or antiproliferative agent into nutritional compositions containing vitamins, minerals and/or other micronutrients, e.g., a multivitamin and mineral preparation.
- the glucarate moiety acts as a carrier for minerals such as calcium and potassium.
- glucarates are included in therapeutic, non-toxic, amounts in a multivitamin supplement as a preventive measure to protect the general population against the onset of hypercholesterolemia and/or cellular hyperproliferation.
- Such formulas may be prepared according to manufacturing techniques well know in the pharmaceutical art, and in a variety of dosage forms, such as, tablets, capsules, and liquids or sustained release formulations thereof.
- glucaric acid and/or glucarates are incorporated in therapeutic amounts into foodstuffs and are consumed by the general population.
- many foodstuffs are enriched by the addition of vitamins and mineral supplements, for example, breads, cereals, milk and fruit juices.
- Glucarates may be added to these products in the same conventional manner in which vitamins or minerals are added to enrich foods.
- calcium glucarate or potassium hydrogen glucarate may be added to a food product, thereby advantageously providing both a mineral supplement, e.g., calcium and potassium, and prophylactic protection against the onset of hyperproliferative diseases and hypercholesterolemia.
- the further enrichment of these products with glucaric acid and/or a glucarate will advantageously provide the consuming public with an inexpensive, safe, and convenient alternative for preventing the onset of hyperproliferative diseases and hypercholesterolemia.
- glucarates are safe, effective hypocholesterolemic and antiproliferation agents.
- glucarate is preferably utilized or administered in combination with a multivitamin and mineral formulation.
- a formulation is administered as a single sustained release dose.
- Calcium D-glucarate was incorporated to the AIN-76A diet (18, 19) at the concentration of 17.5 or 35 mmol/kg diet with no changes in the level of any essential micronutrient. Specifically there was no change in the level of calcium and phosphorus.
- the AIN-76A or glucarate-containing AIN-76A diets were fed ad libitum to female Sprague-Dawley rats beginning at 40 days of age. Food intake and body weight were monitored periodically. There was no statistically significant difference in food intake or weight gain. DNA labeling indices were measured in 55-day-old rats. Four animals from each dietary group were injected at 9:00 a.m.
- the blood serum was obtained from rats and analyzed for their total cholesterol, triglycerides and lipoprotein cholesterol (21).
- the test methodologies all run on a Roche Cobas Mira according to the procedure recommended by manufacturer, were as follows. Total cholesterol was assayed using a sequential enzymatic reaction forming a quinoneimmine dye in one step. Triglycerides in serum were hydrolyzed by lipase to free fatty acids and glycerol to form red chromogen.
- HDL was separated by isoelectric-polyanionic precipitation of LDL, using phosphotungstate as precipitation reagent.
- HDL cholesterol (HDL-C) was then assayed as described above for total cholesterol.
- dietary glucarate significantly and in a dose dependent fashion reduced serum levels of total cholesterol.
- the LDL cholesterol reduction by glucarate (35 mmol/kg diet) was also significant. There were no significant differences in triglyceride, HDL-C or VLDL-C levels.
- Rats Six week-old male Sprague-Dawley rats received a single subcutaneous injection of azoxymethane (15mg/kg body weight) (22). Rats were fed normal chow diets containing 140 mmol/kg of either calcium glucarate or calcium gluconate (negative calcium control) beginning 1 week before carcinogen administration. Animals were sacrificed 8 months post-carcinogen treatment and evaluated for the presence of tumors.
- the contents of the AIN-76 Mineral Mixture and the AIN-76A Vitamin Mixture are shown in Tables 4 and 5, respectively. These mineral and vitamin mixtures, known from the prior art, were used to prepare the AIN-76A diet used as control diet in Example 1.
- a normal fat diet (pelleted corn starch AIN-76A diet) and a high fat diet containing 5% and 20% fat, respectively, were prepared as described in the prior art (Dyets, Inc. 1981/1988 catalog: Experimental Diets & Ingredients for Laboratory Animals).
- Two high fat diets were prepared by incorporating potassium hydrogen D-glucarate at the concentration of 17 or 34 mmol/kg diet using the mineral formulas 3 and 4 as described in Example 4 (see Table 6).
- Female virgin Sprague-Dawley rats were fed these experimental diets or control diets for 4 weeks beginning at 44 days of age. The rats were sacrificed and the blood was assayed for total cholesterol, total triglycerides, HDL-C, LDL-C and VLDL-C as described in Example 1. The results are shown in Table 8.
- the hypercholesterolemic high fat diet increased the serum levels of total cholesterol and LDL cholesterol 1.2-fold and 2.3-fold, respectively. However, the increased total cholesterol and LDL cholesterol levels were reduced 12% (p ⁇ 0.05) and 35% (0.02) respectively by using the glucarate mineral Formula 3 of Example 4 (34 mmol glucarate per kg high fat diet).
- Table 11 shows the vitamin and mineral content of a pharmaceutical formula with glucarate provided in the form of potassium hydrogen D-glucarate.
- Table 14 The contents of a chemically defined diet with glucarate is shown in Table 14. This is an example of a nutritionally complete, elemental diet for enteral nutrition. Table 15 describes acceptable ranges of these components.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Inorganic Chemistry (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
TABLE 1 ______________________________________ Effect of Dietary Glucarate on Serum Cholesterol Levels in Female Sprague-Dawley Rats.sup.a Glucarate-Containing AIN-76A AIN-76A 17.5 mmol/kg 35 mmol/kg ______________________________________ Total cholesterol 110.8 ± 2.7 100.3 ± 4.0.sup.b 95.2 ± 3.7.sup.c Total Triglycerides 56.7 ± 4.8 54.7 ± 3.5 51.4 ± 4.1 HDL-C.sup.d 87.3 ± 3.6 82.9 ± 3.9 79.8 ± 3.4 LDL-C.sup.e 9.6 ± 0.9 6.7 ± 1.3 6.6 ± 0.9.sup.f VLDL-C.sup.g 10.7 ± 0.9 10.7 ± 0.7 9.3 ± 0.7 ______________________________________ .sup.a Each value is the mean (mg/dl) ± S.E., n = 9 per group. .sup.b Significantly different from the AIN76A value: 10% reduction, p<0.05. .sup.c Significantly different from the AIN76A value: 14% reduction, p<0.002. .sup.d HDLC = high density lipoprotein cholesterol. .sup.e LDLC = low density lipoprotein cholesterol. .sup.f Significantly different from the AIN76A value: 30% reduction, p<0.05. .sup.g VLDLC = very low density lipoprotein cholesterol.
TABLE 2 ______________________________________ Cytokinetics of Colonic and Small Intestine Mucosa in 55-Day-Old Female Sprague-Dawley Rats Fed AIN-76A and Glucarate-Containing AIN-76A Diets.sup.a Colon Small Intestine AIN-76A + AIN-76A + AIN-76A Glucarate.sup.b AIN-76A Glucarate.sup.b ______________________________________ Crypt 33.1 ± 0.6 32.7 ± 0.6 81.4 ± 1.3 90.9 ± 1.4 column height (cells) Labeling 4.4 ± 0.5 2.8 ± 0.2.sup.c 9.4 ± 0.3 7.1 ± 0.4.sup.d index (per crypt column) Highest 6.1 ± 0.7 5.1 ± 0.6.sup.c 19.7 ± 1.5 14.8 ± 1.6.sup.e labeled cell position ______________________________________ .sup.a Mean ± S.E. .sup.b 35 mmol/kg diet. .sup.c 36% reduction, p<0.005. .sup.d 25% reduction, p<0.0005. .sup.e p< 0.025.
TABLE 3 __________________________________________________________________________ Inhibition of Azoxymethane-Induced Colon Tumorigenesis by Dietary Glucarate Rats with Tumors (%) Tumors per Rat No. of Small Small Treatment Rats Intestine Colon Total Intestine Colon Total __________________________________________________________________________ Calcium 17 2(11.7) 8(47.0) 10(58.8) 0.12 ± 0.10 0.53 ± 0.05 0.65 ± 0.07 Gluconate.sup.a (Control) Calcium 16 0 1(6.2).sup.b 1(6.2).sup.b 0 0.06 ± 0.01.sup.c 0.06 ± 0.01.sup.c Glucarate.sup.a __________________________________________________________________________ .sup.a 140 mmol/kg diet. .sup.b Significantly different from control group: p<0.005. .sup.c Significantly different form control group: p<0.05.
TABLE 4 ______________________________________ AIN-76 Mineral Mixture.sup.a Ingredient g/kg mixture ______________________________________ Calcium phosphate, dibasic (CaHPO.sub.4) 500.00 Sodium chloride (NaCl) 74.00 Potassium citrate, monohydrate 220.00 (K.sub.3 C.sub.6 H.sub.5 O.sub.7.H.sub.2 O) Potassium sulfate (K.sub.2 SO.sub.4) 52.00 Magnesium oxide (MgO) 24.00 Manganum carbonate (43-48% Mn 3.50 Ferric citrate (16-17% Fe) 6.00 Zinc carbonate (70% ZnO) 1.60 Cupric carbonate (53-55% Cu) 0.30 Potassium iodate (KIO.sub.3) 0.01 Sodium selenite (Na.sub.2 SeO.sub.3.5H.sub.2 O) 0.01 Chromium potassium sulfate 0.55 (CrKSO.sub.4.12H.sub.2 O) Sucrose, finely powdered 118.00 ______________________________________ .sup.a To be used at 3.5% of the diet (Journal of Nutrition 107:1340-1348 1977).
TABLE 5 ______________________________________ AIN-76 Vitamin Mixture.sup.a Vitamin g/kg mixture ______________________________________ Thiamine.HCl 0.60 Riboflavin 0.60 Pyridoxine.HCl 0.70 Niacin 3.00 Calcium Pantothenate 1.60 Folic acid 0.20 D-Biotin 0.02 Vitamin B.sub.12 (0.1%) 1.00 Retinyl palmitate (500,000 U/g) 0.80 d1-α-Tocopherol acetate (500 U/g) 10.00 Cholecalciferol (400,000 U/g) 0.25 Menadione sodium bisulfite 0.08 Sucrose, finely powdered 981.15 ______________________________________ .sup.a To be used at 1% of diet (Journal of Nutrition 107:1340-1348, 1977 110:1726, 1980).
TABLE 6 __________________________________________________________________________ Glucarate-Containing Mineral Formulas.sup.a g/kg mixture Ingredient Formula 1 Formula 2 Formula 3 Formula 4 __________________________________________________________________________ Calcium phosphate, dibasic (CaHPO.sub.4) 366.00 433.00 500.00 500.00 Calcium D-glucarate (CaC.sub.6 H.sub.8 O.sub.8.3.5H.sub.2 O) 300.00 150.00.sup.c -- -- Sodium chloride (NaCl) 74.00 74.00 74.00 74.00 Potassium citrate, monohydrate -- 110.00 100.00 168.00 (K.sub.3 C.sub.6 H.sub.5 O.sub.7.H.sub.2 O) Potassium phosphate dibasic (K.sub.2 HPO.sub.4) 172.00 86.00 -- -- Potasium hydrogen Dglucarate -- -- 238.00.sup.b 119.00.sup.c (KC.sub.6 H.sub.7 O.sub.8) Potassium sulfate (K.sub.2 SO.sub.4) 52.00 52.00 52.00 52.00 Magnesium oxide (MgO) 24.00 24.00 24.00 24.00 Magnesium carbonate (43-48% Mn) 3.50 3.50 3.50 3.50 Ferric citrate (16-17% Fe) 6.00 6.00 6.00 6.00 Zinc carbonate (70% ZnO) 1.60 1.60 1.60 1.60 Cupric carbonate (53-55% Cu) 0.30 0.30 0.30 0.30 Potassium iodate (KIO.sub.c) 0.01 0.01 0.01 0.01 Sodium selenite (Na.sub.2 SeO.sub.3.5H.sub.2 O) 0.01 0.01 0.01 0.01 Chromium potassium sulfate 0.55 0.55 0.55 0.55 (CrKSO.sub.4.12H.sub.2 O) Sucrose, finely powdered -- 59.00 -- 51.00 __________________________________________________________________________ .sup.a To be used at 3.5% of the diet. .sup.b 34 mmoles of glucarate per kg diet. .sup.c 17 mmoles of glucarate per kg diet.
TABLE 7 __________________________________________________________________________ Effect of Dietary Glucarate on DNA Labeling Index in Female Virgin Sprague-Dawley Rats Content Labeling Index (% or per colon crypt).sup.a (mmol/kg diet) Mammary Gland Urinary Diet Glucarate Calcium Buds Ducts Colon Bladder __________________________________________________________________________ AIN-76A None 130 19.97 ± 1.25.sup.a 13.42 ± 1.19 11.12 ± 0.89 0.51 ± 0.12.sup.a AIN-76A + None 200 15.27 ± 0.66 7.60 ± 0.57 8.21 ± 1.01 0.36 ± 0.08.sup.a Ca Tartrate AIN-76 A + 70 200 2.85 ± 0.90 0.57 ± 0.15 4.58 ± 0.36.sup.a 0.32 ± 0.04.sup.a Ca Glucarate Modified AIN-76A 34 130 0.81 ± 0.15 0.24 ± 0.10 4.19 ± 0.54.sup.a 0.08 ± 0.04 with glucarate __________________________________________________________________________ .sup.a Mean ± Student's ttests were performed in all possible diet comparisons. For all comparisons but those marked with asterisks, the differences were significant (the pvalues ranged from 0.0005 to 0.025).
TABLE 8 __________________________________________________________________________ Effect of Dietary Glucarate on Serum Cholesterol Levels.sup.a in Female Sprague-Dawley Rats Fed Hypercholesterolemic Diets Glucarate Fat Total Total Diet (mmol/kg diet) (%) Cholesterol TriGlycerides HDL-C.sup.b LDL-C.sup.c VLDL-C.sup.d __________________________________________________________________________ NFD.sup.e None 5 87.0 ± 5.6 26.8 ± 4.8 71.8 ± 7.7 10.0 ± 2.2 5.1 ± 1.1 HFD.sup.f None 20 105.6 ± 4.5 31.0 ± 2.4 76.1 ± 3.8 23.3 ± 1.4 6.1 ± 0.4 HFD with 34 20 92.4 ± 4.1.sup.g 25.7 ± 1.7 72.3 ± 3.3 15.1 ± 1.4.sup.h 5.0 ± 0.3 Glucarate HFD with 17 20 101.3 ± 5.4 32.1 ± 3.7 73.4 ± 3.1 21.6 ± 2.1 6.3 ± 0.8 glucarate __________________________________________________________________________ .sup.a Each value is the mean (mg/dl) ± S.E.; n = 7. .sup.b HDLC = high density lipoprotein cholesterol. .sup.c LDLC = low density lipoprotein cholesterol. .sup.d VLDLC = Very low density lipoprotein cholesterol. .sup.e NFD = normal fat diet (corn starch AIN76A diet; J. Nutr. 107:1341, 1977; 110:1726, 1980) containing 5% corn oil. .sup.f HDF = high fat diet containing 20% corn oil. .sup.g Significantly different from the high fat diet value: 12% reductio (p<0.05). .sup.h Significantly different from the high fat diet value: 35% reductio (p<0.02).
TABLE 9 ______________________________________ Chemical Content of Two Pharmaceutical Formulas with Glucarate Amount.sup.b Active Ingredient Formula 1.sup.c Formula 2.sup.d ______________________________________ Cholecalciferol 1.25 μg 1.25 μg Calcium Phosphate, dibasic 374.15 mg 374.15 mg (CaHPO.sub.4) Calcium D-glucarate 320.20 mg 320.20 mg (CaC.sub.6 H.sub.8 O.sub.8 4 H.sub.2 O) Potassium phosphate, dibasic 363.50 mg 169.00 mg (K.sub.2 HPO.sub.4) Magnesium oxide 83.90 mg 82.90 mg (MgO) ______________________________________ .sup.a For vitamin and mineral content see Table 10. .sup.b Per tablet, capsule, caplet or wafer. .sup.c Calcium to phosphorus ratio 1 to 1. .sup.d Calcium to phosphorus ratio 1.3 to 1.
TABLE 10 __________________________________________________________________________ Vitamin and Mineral Content of Two Pharmaceutical Formulas with Glucarate.sup.a Formula 1.sup.b Formula 2.sup.c Vitamin or Mineral Amount.sup.d % U.S. RDA.sup.e Amount.sup.d % U.S. RDA.sup.e __________________________________________________________________________ Vitamin D 50 IU 12.5 50 IU 12.5 Calcium 150 mg 12.5 150 mg 12.5 Phosphorus 150 mg 12.5 115 mg 9.6 Magnesium 50 IU 12.5 50 mg 12.5 Potassium 163 mg N.D..sup.f 76 mg N.D..sup.f Glucarate 209 mg N.D..sup.f 209 mg N.D..sup.f __________________________________________________________________________ .sup.a For chemical content see Table 9. .sup.b Calcium to phosphorus ratio 1 to 1. .sup.c Calcium to phosphorus ratio 1.3 to 1. .sup.d Per tablet, capsule, caplet or wafer. The highest recommended dose (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C. 1989). .sup.e U.S. Recommended Daily Allowances has not been established. .sup.f N.D. = Not Determined.
TABLE 11 ______________________________________ A Vitamin and Mineral Pharmaceutical Formula with Glucarate Vitamin or Mineral Amount.sup.a % U.S. RDA.sup.b ______________________________________ Vitamin D.sup.c 50 IU 12.5 Calcium.sup.d 150 mg 12.5 Phosphorus.sup.e 115 mg 12.5 Magnesium.sup.f 50 mg 12.5 Potassium.sup.g 39 mg N.D..sup.h Glucarate.sup.g 209 mg N.D..sup.h ______________________________________ .sup.a Per tablet, capsule, caplet or wafer. .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C., 1989). .sup.c As cholecalciferol (1.25 μg). .sup.d As calcium phosphate, dibasic (510.2 mg). .sup.e As calcium phosphate, dibasic (see above). Calcium to phosphate ratio 1.3 to 1. .sup.f As magnesium oxide (82.90 mg). .sup.g As potassium hydrogen Dglucarate (248.2 mg). .sup.h N.D. = Not Determined.
TABLE 12 ______________________________________ A Multi-Vitamin and Multi-Mineral Formula with Glucarate Vitamin, Mineral or Trace Element Amount.sup.a % U.S. RDA.sup.b ______________________________________ Vitamin A.sup.c 162.5 RE 12.5 Vitamin D.sup.d 50.0 IU 12.5 Vitamin E.sup.e 1.5 α-TE 12.5 Vitamin K 10.0 μg 12.5 Vitamin C 12.0 mg 12.5 Thiamin 0.2 mg 12.5 Riboflavin 225.0 μg 12.5 Niacin.sup.f 2.5 NE 12.5 Vitamin B.sub.6 275.0 μg 12.5 Folate 50.0 μg 12.5 Vitamin B.sub.12 325.0 ng 12.5 Biotin 12.5 μg 12.5.sup.g Panthothenic acid 875.0 μg 12.5 Calcium.sup.h 150.0 mg 12.5 Phosphorus.sup.i 150.0 mg 12.5 Magnesium 50.0 mg 12.5 Iron 3,750.0 μg 12.5 Zinc 1,875.0 μg 12.5 Iodine 25.0 μg 12.5 Selenium 9.5 μg 12.5 Copper 375.0 μg 12.5.sup.g Manganese 625.0 μg 12.5.sup.g Fluoride 500.0 μg 12.5.sup.g Chromium 25.0 μg 12.5.sup.g Molybdenum 32.0 μg 12.5.sup.g Potassium.sup.j 163.0 mg N.D..sup.k Glucarate.sup.l 209.0 mg ______________________________________ .sup.a Per tablet, capsule, caplet or wafer. .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C., 1989). .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6 μg carotene or an equivalent amount of a retinoic acid compound. .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of vitamin D .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol. .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin. .sup.g The highest estimated safe or adquate dose (ibid.). .sup.h As calcium phosphate, dibasic (374.15 mg) and calcium Dglucarate tetrahydrate (320.2 mg). .sup.i As calcium phosphate, dibasic (see above) and potassium phosphate, dibasic (363.50 mg). Calcium to Phosphorus ratio 1 to 1. .sup.j As potassium phosphate, dibasic (see above). .sup.k N.D. = Not Determined. .sup.l As calcium Dglucarate (see above).
TABLE 13 ______________________________________ A High Potency Multi-Vitamin and Mineral Formula with Glucarate Vitamin or Mineral Amount.sup.a % U.S. RDA.sup.b ______________________________________ Vitamin A.sup.c 1,300.0 RE 100 Vitamin D.sup.d 400.0 IU 100 Vitamin E.sup.e 48.0 α-TE 400 Vitamin C 768.0 mg 800 Thiamin 40.0 mg 2500 Riboflavin 4,140.0 μg 230 Niacin.sup.f 40.0 NE 200 Vitamin B.sub.6 44.0 mg 2000 Folate 400.0 μg 100 Vitamin B.sub.12 41.6 μg 1600 Pantothenic acid 56.0 mg .sup. 800.sup.g Calcium.sup.h 600.0 mg 50 Phosphorus.sup.i 600.0 mg 50 Magnesium 200.0 mg 50 Zinc 15.0 mg 100 Selenium 76.0 μg 100 Potassium.sup.j 652.0 mg N.D..sup.k Glucarate 832.0 mg N.D..sup.k ______________________________________ .sup.a Per four tablets or packets. .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C., 1989). .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6μ carotene, or an equivalent amount of a retinoic acid compound. .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of Vitamin D .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol. .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin. .sup.g The highest estimated safe or adequate dose (ibid.). .sup.h As calcium phosphate, dibasic (1,496.6 mg) and calcium Dglucarate, tetrahydrate, (1,280.0 mg). .sup.i As calcium phosphate, dibasic (see above) and potassium phosphate, dibasic (1,454.0 mg). Calcium to phosphorus ratio 1 to 1. .sup.j As potassium phosphate, dibasic (see above). .sup.k N.D. = Not Determined. .sup.l As calcium Dglucarate (see above).
TABLE 14 ______________________________________ A Chemically Defined Diet with Glucarate Ingredient Amount.sup.a % U.S. RDA.sup.b ______________________________________ Macroconstituents: Amino Acids (Free) 37.1 g Carbohydrates 407.4 g (Predisgested) Fat 2.6 g Linoleic acid 2.1 g Vitamins, Minerals, Electro- lytes, Trace Elements: Vitamin A.sup.c 1300.0 RE 100 Vitamin D.sup.d 400.0 IU 100 Vitamin E.sup.e 12.0 α-TE 100 Vitamin K 80.0 mg 100 Vitamin C 96.0 mg 100 Thiamin 1.6 mg 100 Riboflavin 1.8 mg 100 Niacin.sup.f 20.0 NE 100 Vitamin B.sub.6 2.2 mg 100 Folate 400.0 μg 100 Vitamin B.sub.12 2.6 mg 100 Biotin 100.0 μg .sup. 100.sup.g Pantothenic acid 7.0 mg .sup. 100.sup.g Calcium.sup.h 1,200.0 mg 100 Phosphorus.sup.i 1,200.0 mg 100 Magnesium 400.0 mg 100 Iron 30.0 mg 100 Zinc 15.0 mg 100 Iodine 200.0 μg 100 Selenium 75.0 μg 100 Copper 3.0 mg .sup. 100.sup.g Manganese 5.0 mg .sup. 100.sup.g Fluoride 1.0 μg .sup. 100.sup.g Chromium 200.0 μg .sup. 100.sup.g Molybdenum 250.0 μg .sup. 100.sup.g Choline 73.3 mg .sup. N.D..sup.j Sodium 842.4 mg N.D. Potassium.sup.k 2,110.0 mg N.D. Chloride 1,710.0 mg N.D. Acetate 995.0 mg N.D. Glucarate.sup.l 3,525.0 mg N.D. ______________________________________ .sup.a Per six packets. One packet to be diluted with water to a total standard dilution volume of 300 ml. .sup.b The highest dose recommended (Recommended Dietary Allowances, 10th Edition, NAP, Washington, D.C., 1989). .sup.c 1 Retinol Equivalent (RE) = 1 μg retinol or 6 μg carotene or an equivalent amount of a retinoic acid compound. .sup.d As cholecalciferol. 10 μg cholecalciferol = 400 IU of vitamin D .sup.e Tocopherol Equivalent (TE) = 1 mg dtocopherol. .sup.f 1 Niacin Equivalent (NE) = 1 mg of niacin. .sup.g The highest estimated safe or adquate dose (ibid.). .sup.h As calcium phosphates. .sup.i As calcium and potassium phosphates. .sup.j N.D. = Not Determined. .sup.k As potassium phosphate and potassium hydrogen Dglucarate. .sup.l As potassium hydrogen Dglucarate.
TABLE 15 ______________________________________ A Chemically Defined Diet with Glucarate ______________________________________ 7-15% by weight of Amino Acids 76-86% by weight of Carbohydrates 0.4-1.2% by weight of Fat 0.4-1.0% by weight of Linoleic acid, and 1,200.0-1,800.0 RE of Vitamin A 400.0-600.0 IU of Vitamin D 12.0-18.0 α-TE of Vitamin E 80.0-120.0 mg of Vitamin K 96.0-480.0 mg of Vitamin C 1.6-3.2 mg of Thiamin 1.8-3.6 mg of Riboflavin 20.0-40.0 NE of Niacin 2.2-4.4 mg of Vitamin B.sub.6 400.0-800.0 μg of Folate 2.6-5.2 mg of Vitamin B.sub.12 100.0-200.0 μg of Biotin 7.0-14.0 mg of Pantothenic acid 1,000.0-1,200.0 mg of Calcium 1,000.0-1,200.0 mg of Phosphorus 350.0-400.0 mg of Magnesium 15.0-30.0 mg of Iron 15.0-22.5 mg of Zinc 150.0-200.0 μg of Iodine 50.0-150.0 μg of Selenium 2.0-3.0 mg of Copper 2.0-5.0 mg of Manganese 0-4.0 mg of Fluoride 0-200.0 μg of Chromium 0-250.0 μg of Molybdenum 72.0-720.0 mg of Choline 840.0-845.0 mg of Sodium 2,110.0-2,400.0 mg of Potassium 1,620.0-1,710.0 mg of Chloride, 0-1,000.0 mg of Acetate, and 1,750.0-7,050.0 mg of Glucarate. ______________________________________
Claims (12)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/012,145 US5364644A (en) | 1990-05-16 | 1993-01-28 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
US08/317,790 US5561160A (en) | 1990-05-16 | 1994-10-04 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52538490A | 1990-05-16 | 1990-05-16 | |
US08/012,145 US5364644A (en) | 1990-05-16 | 1993-01-28 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US52538490A Continuation | 1990-05-16 | 1990-05-16 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/317,790 Division US5561160A (en) | 1990-05-16 | 1994-10-04 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
US5364644A true US5364644A (en) | 1994-11-15 |
Family
ID=24093031
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/012,145 Expired - Lifetime US5364644A (en) | 1990-05-16 | 1993-01-28 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
US08/317,790 Expired - Lifetime US5561160A (en) | 1990-05-16 | 1994-10-04 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/317,790 Expired - Lifetime US5561160A (en) | 1990-05-16 | 1994-10-04 | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Country Status (7)
Country | Link |
---|---|
US (2) | US5364644A (en) |
EP (2) | EP0730862A1 (en) |
JP (1) | JPH06504259A (en) |
AT (1) | ATE142489T1 (en) |
CA (1) | CA2080818A1 (en) |
DE (1) | DE69122099T2 (en) |
WO (1) | WO1991018593A1 (en) |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5561160A (en) * | 1990-05-16 | 1996-10-01 | Walaszek; Zbigniew | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
US5626884A (en) * | 1995-08-18 | 1997-05-06 | Lockett; Curtis G. | Treatment of sickle cell disease |
US5891459A (en) * | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US6069167A (en) * | 1996-01-16 | 2000-05-30 | University Technology Corporation | Use of antioxidant agents to treat cholestatic liver disease |
US6103733A (en) * | 1998-09-09 | 2000-08-15 | Bachmann; Kenneth A. | Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes |
US6203818B1 (en) | 1997-03-20 | 2001-03-20 | Coventry Group, Ltd. | Nutritional supplement for cardiovascular health |
US6368640B1 (en) | 1998-04-03 | 2002-04-09 | The Daily Wellness Company | Method and composition for improving sexual fitness |
US6497885B2 (en) | 2000-12-22 | 2002-12-24 | The Daily Wellness Company | Method and composition for improving fertility health in female and male animals and humans |
US6596762B2 (en) | 2001-05-17 | 2003-07-22 | The Regents Of The University Of Colorado | Antioxidant compositions and use for treatment of hepatic steatosis and steatohepatitis |
US20040074504A1 (en) * | 1999-06-05 | 2004-04-22 | Cooke John P. | Method and composition for inhibiting cardiovascular cell proliferation |
US20050192210A1 (en) * | 2004-03-01 | 2005-09-01 | Rothbard Jonathan B. | Compositions and methods for treating diseases |
US6989164B2 (en) | 2000-12-22 | 2006-01-24 | The Daily Wellness Company | Method and composition for improving male fertility health |
US7371415B1 (en) | 1998-04-03 | 2008-05-13 | The Daily Wellness Company | Method and composition for improving sexual fitness |
US20090131259A1 (en) * | 2007-11-15 | 2009-05-21 | Kiely Donald E | Hydroxypolyamide Gel Forming Agents |
US20090250653A1 (en) * | 2006-08-07 | 2009-10-08 | Kiely Donald E | Hydroxycarboxylic Acids and Salts |
US20100247505A1 (en) * | 2007-10-25 | 2010-09-30 | Nutri Co., Ltd. | Composition for Reducing the Level of Glucose, Malondialdehyde-Modified LDL, Homocysteine and/or C-Reactive Protein in Blood |
US9096787B2 (en) | 2012-11-28 | 2015-08-04 | Rivertop Renewables | Corrosion inhibiting, freezing point lowering compositions |
US9162959B2 (en) | 2006-08-07 | 2015-10-20 | The University Of Montana | Method of oxidation using nitric acid |
US9187398B2 (en) | 2013-03-13 | 2015-11-17 | Rivertop Renewables, Inc. | Nitric acid oxidation processes |
US9346736B2 (en) | 2013-03-13 | 2016-05-24 | Rivertop Renewables, Inc. | Oxidation process |
US9347024B2 (en) | 2011-04-21 | 2016-05-24 | Rivertop Renewables, Inc. | Calcium sequestering composition |
US9404188B2 (en) | 2010-11-11 | 2016-08-02 | Rivertop Renewables | Corrosion inhibiting composition |
US9670124B2 (en) | 2013-03-13 | 2017-06-06 | Rivertop Renewables, Inc. | Nitric acid oxidation process |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2693876A1 (en) * | 1992-07-24 | 1994-01-28 | Vani | Micro-nutrient compsn. to combat the effects of stress - contains B vitamin(s), octacosanol, calcium, magnesium, chromium and zinc and opt. other micro-nutrients |
BE1006217A6 (en) * | 1992-09-10 | 1994-06-14 | Steils Anne Epouse Gerome | Milky drink enhanced nutrient. |
CA2089607C (en) * | 1992-11-05 | 1997-11-04 | Ranjit K. Chandra | Nutritional supplement for the elderly |
WO1995035038A1 (en) * | 1994-06-20 | 1995-12-28 | Peter Singer | Dietetic foodstuff and its use |
CA2277333A1 (en) * | 1997-01-27 | 1998-07-30 | Takara Shuzo Co., Ltd. | Tetrahydrofuran derivatives |
ITFI970184A1 (en) * | 1997-07-30 | 1999-01-30 | Menarini Farma Ind | PHARMACEUTICAL COMPOSITIONS CONTAINING VITAMIN D AND CALCIUM, THEIR PREPARATION AND THERAPEUTIC USE |
GB2337933A (en) * | 1998-06-04 | 1999-12-08 | Stephen Bloor | Treating or prophylaxis of smoking related diseases |
US6245360B1 (en) * | 1998-06-26 | 2001-06-12 | John S. Markowitz | Nutritional supplement |
AU4988000A (en) * | 1999-05-07 | 2000-11-21 | Trustees Of Tufts College | Immune stimulating dietary supplement and methods of use thereof |
EP1209987A1 (en) * | 1999-08-17 | 2002-06-05 | Jaroslav Hanzel | Composition for preventing iodine deficiency |
GB0016452D0 (en) * | 2000-07-04 | 2000-08-23 | Kilgowan Limited | Vitamin K and essential fatty acids |
ES2168226B1 (en) * | 2000-11-27 | 2003-09-16 | Recuperat Ion Electrolitos S L | COMPOSITION THAT INCLUDES SODIUM, POTASSIUM, CALCIUM AND MAGNESIUM. |
US6849613B2 (en) * | 2001-08-29 | 2005-02-01 | Kedar N. Prasad | Multiple antioxidant micronutrients |
US6562378B1 (en) * | 2002-08-16 | 2003-05-13 | Tsar Health Private Ltd. | Nutritional supplement for adolescents |
US6565891B1 (en) * | 2002-08-23 | 2003-05-20 | Tsar Health Private Ltd. | Nutritional supplement for children |
US20080020035A1 (en) * | 2002-08-28 | 2008-01-24 | Kedar Prasad | Micronutrient formulations and related methods of manufacture |
US7635469B2 (en) * | 2002-08-28 | 2009-12-22 | Premier Micronutrient Corporation | Micronutrient formulations for hearing health |
GB2416981A (en) * | 2004-08-13 | 2006-02-15 | Nutraceuticals Ltd | Premixes, flour enriched with same, mineral supplemented foodstuffs and methods of manufacture therefore. |
US7628984B2 (en) * | 2005-02-17 | 2009-12-08 | Premier Micronutrient Corporation | Micronutrient formulations for pulmonary and heart health |
DE102006040456A1 (en) * | 2006-08-25 | 2008-02-28 | Constantin Nies | Planar solid dosage form of nutritional supplements and/or drugs, useful for the supplementation of finished or semi-finished foods, where the planar solid dosage form is e.g. cookies, cracker, soda dough products and gingerbread |
US7605145B2 (en) * | 2006-11-20 | 2009-10-20 | Premier Micronutrient Corporation | Micronutrient formulations for treatment of diabetes mellitus |
US10499682B2 (en) | 2014-08-25 | 2019-12-10 | New Age Beverage Corporation | Micronutrient formulation in electronic cigarettes |
EP4025075A1 (en) * | 2019-09-05 | 2022-07-13 | Société des Produits Nestlé S.A. | Food compositions for lactating women |
JP2022546966A (en) * | 2019-09-05 | 2022-11-10 | ソシエテ・デ・プロデュイ・ネスレ・エス・アー | Food composition for lactating women |
US11278520B2 (en) * | 2020-03-31 | 2022-03-22 | Sabine Hazan | Method of preventing COVID-19 infection |
Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1066885A (en) * | 1964-07-29 | 1967-04-26 | Zh Tokyo Seikagaku Kenkyukai | Therapeutic agent and compositions having the inhibitory action for ª‰-glucuronidase and method of inhibiting ª‰-glucuronidase |
US3697287A (en) * | 1969-01-28 | 1972-10-10 | Morton Norwich Products Inc | Amino acid food composition |
NL7712421A (en) * | 1976-11-13 | 1978-05-17 | Koehler Valentin | PROCESS FOR PREPARING AN AGENT WITH PHARMACEUTICAL AND / OR ANTI-MICROBIAL ACTION. |
DE2651947A1 (en) * | 1976-11-13 | 1978-05-18 | Koehler Valentin | Compsns. contg. glucaric acid or its derivs. - useful as antibacterial and antifungal medicaments, food preservatives, microbicides and disinfectants |
US4740373A (en) * | 1986-05-27 | 1988-04-26 | Usv Pharmaceutical Corporation | Stabilization of multivitamin/trace elements formulations |
US4751085A (en) * | 1984-08-29 | 1988-06-14 | Gaull Gerald E | Human nutritional compositions containing taurine and vitamins and/or minerals |
US4845123A (en) * | 1985-08-05 | 1989-07-04 | The Ohio State University | Reduction in vivo of the inappropriate levels of endogenous and environmental-derived compounds by sustained-release inhibitors of β-g |
US4997852A (en) * | 1987-08-26 | 1991-03-05 | Ohio State University Research Foundation | Method and composition for achieving cancer chemopreventive and chemotherapeutic activity |
US5008291A (en) * | 1987-08-26 | 1991-04-16 | Ohio State University Research Foundation | Method and composition for achieving chemotherapeutic activity |
US5010107A (en) * | 1987-08-26 | 1991-04-23 | Ohio State University Research Foundation | Method and composition for achieving anticarcinogenic activity |
WO1991018593A1 (en) * | 1990-05-16 | 1991-12-12 | Board Of Regents, The University Of Texas System | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
-
1991
- 1991-05-15 EP EP96200094A patent/EP0730862A1/en not_active Withdrawn
- 1991-05-15 EP EP91910048A patent/EP0528950B1/en not_active Expired - Lifetime
- 1991-05-15 WO PCT/US1991/003378 patent/WO1991018593A1/en active IP Right Grant
- 1991-05-15 CA CA002080818A patent/CA2080818A1/en not_active Abandoned
- 1991-05-15 DE DE69122099T patent/DE69122099T2/en not_active Expired - Fee Related
- 1991-05-15 JP JP3509441A patent/JPH06504259A/en active Pending
- 1991-05-15 AT AT91910048T patent/ATE142489T1/en active
-
1993
- 1993-01-28 US US08/012,145 patent/US5364644A/en not_active Expired - Lifetime
-
1994
- 1994-10-04 US US08/317,790 patent/US5561160A/en not_active Expired - Lifetime
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1066885A (en) * | 1964-07-29 | 1967-04-26 | Zh Tokyo Seikagaku Kenkyukai | Therapeutic agent and compositions having the inhibitory action for ª‰-glucuronidase and method of inhibiting ª‰-glucuronidase |
US3697287A (en) * | 1969-01-28 | 1972-10-10 | Morton Norwich Products Inc | Amino acid food composition |
NL7712421A (en) * | 1976-11-13 | 1978-05-17 | Koehler Valentin | PROCESS FOR PREPARING AN AGENT WITH PHARMACEUTICAL AND / OR ANTI-MICROBIAL ACTION. |
DE2651947A1 (en) * | 1976-11-13 | 1978-05-18 | Koehler Valentin | Compsns. contg. glucaric acid or its derivs. - useful as antibacterial and antifungal medicaments, food preservatives, microbicides and disinfectants |
FR2370471A1 (en) * | 1976-11-13 | 1978-06-09 | Kohler Valentin | Compsns. contg. glucaric acid and derivs. - useful as microbicides and pharmaceuticals |
US4751085A (en) * | 1984-08-29 | 1988-06-14 | Gaull Gerald E | Human nutritional compositions containing taurine and vitamins and/or minerals |
US4845123A (en) * | 1985-08-05 | 1989-07-04 | The Ohio State University | Reduction in vivo of the inappropriate levels of endogenous and environmental-derived compounds by sustained-release inhibitors of β-g |
US4740373A (en) * | 1986-05-27 | 1988-04-26 | Usv Pharmaceutical Corporation | Stabilization of multivitamin/trace elements formulations |
US4997852A (en) * | 1987-08-26 | 1991-03-05 | Ohio State University Research Foundation | Method and composition for achieving cancer chemopreventive and chemotherapeutic activity |
US5008291A (en) * | 1987-08-26 | 1991-04-16 | Ohio State University Research Foundation | Method and composition for achieving chemotherapeutic activity |
US5010107A (en) * | 1987-08-26 | 1991-04-23 | Ohio State University Research Foundation | Method and composition for achieving anticarcinogenic activity |
WO1991018593A1 (en) * | 1990-05-16 | 1991-12-12 | Board Of Regents, The University Of Texas System | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
Non-Patent Citations (53)
Title |
---|
Abou Issa et al., Putative Metabolites Derived from Dietary Combinations of Calcium Glucarate and N (4 hydroxyphenyl) Retinamide Act Synergistically to Inhibit the Induction of Rat Mammary Tumors by 7,12 dimethylbenz a anthracene, Proc. Natl. Acad. Sci. USA, 85:4181 4184 (1988) published in USA. * |
Abou-Issa et al., "Putative Metabolites Derived from Dietary Combinations of Calcium Glucarate and N-(4-hydroxyphenyl) Retinamide Act-Synergistically to Inhibit the Induction of Rat Mammary Tumors by 7,12-dimethylbenz[a]anthracene," Proc. Natl. Acad. Sci. USA, 85:4181-4184 (1988) published in USA. |
Alberts et al., "Mevinolin: A Highly Potent Competitive Inhibitor of Hydroxymethylglutaryl-coenzyme A Reductase and a Cholesterol-lowering Agent," Proc. Natl. Acad. Sci. USA, 77(7):3957-3961 (1980), published in USA. |
Alberts et al., Mevinolin: A Highly Potent Competitive Inhibitor of Hydroxymethylglutaryl coenzyme A Reductase and a Cholesterol lowering Agent, Proc. Natl. Acad. Sci. USA, 77(7):3957 3961 (1980), published in USA. * |
Babiak et al., "Effects of Dietary Polyunsaturated and Saturated Fats on Lipoproteins in the Baboon," Atherosclerosis, 57:1-17 (1985), published in Ireland. |
Babiak et al., Effects of Dietary Polyunsaturated and Saturated Fats on Lipoproteins in the Baboon, Atherosclerosis, 57:1 17 (1985), published in Ireland. * |
Boyland et al., "An Attempt to Prevent the Induction of Bladder Cancer in Dogs with 1→4-Gluco-Saccharolactone," Investigative Urology, 2(5):439-445 (1965), published in USA. |
Boyland et al., "Attempted Prophylaxis of Bladder Cancer with 1→4 glucosaccharolactone," British Journal of Urology, 36:563-569 (1964), published in United Kingdom. |
Boyland et al., An Attempt to Prevent the Induction of Bladder Cancer in Dogs with 1 4 Gluco Saccharolactone, Investigative Urology, 2(5):439 445 (1965), published in USA. * |
Boyland et al., Attempted Prophylaxis of Bladder Cancer with 1 4 glucosaccharolactone, British Journal of Urology, 36:563 569 (1964), published in United Kingdom. * |
Bradley, "Effect of a β-Glucuronidase Inhibitor and Methylcholanthrene on the Induction of Bladder Tumors in Rats," the Journal of Urology, 55(5):626-628 (1962), published in USA. |
Bradley, Effect of a Glucuronidase Inhibitor and Methylcholanthrene on the Induction of Bladder Tumors in Rats, the Journal of Urology, 55(5):626 628 (1962), published in USA. * |
Furuno et al., "Effect of D-Glucarates on Basic Antiobiotic-Induced Renal Damage in Rats," Chemical Abstracts, 84:41 (1976), Abstract No. 115903y, published in USA. |
Furuno et al., "Preventive Effect of D-Glucarate against Renal Damage Induced by Kanamycin," Chemical Abstracts, 85:45 (1976), Abstract No. 154048p, published in USA. |
Furuno et al., Effect of D Glucarates on Basic Antiobiotic Induced Renal Damage in Rats, Chemical Abstracts, 84:41 (1976), Abstract No. 115903y, published in USA. * |
Furuno et al., Preventive Effect of D Glucarate against Renal Damage Induced by Kanamycin, Chemical Abstracts, 85:45 (1976), Abstract No. 154048p, published in USA. * |
Garrison and Somer, "Vitamins and Minerals: Their Relationship to Cardiovascular Disease," the Nutrition Desk Reference, Keats Publishing, Inc., New Canaan, Conn., Chapter 14, pp. 172-180 (1985), published in USA. |
Garrison and Somer, Vitamins and Minerals: Their Relationship to Cardiovascular Disease, the Nutrition Desk Reference, Keats Publishing, Inc., New Canaan, Conn., Chapter 14, pp. 172 180 (1985), published in USA. * |
Iida et al., "2,5-DI-O-Acetyl-D-Glucosaccharo-(1-4), (6-8)-Dilactone, A New Potent β-Glucuronidase Inhibitor," Jap. J. Pharmacol., 15:88-90 (1955), published in Japan. |
Iida et al., 2,5 DI O Acetyl D Glucosaccharo (1 4), (6 8) Dilactone, A New Potent Glucuronidase Inhibitor, Jap. J. Pharmacol., 15:88 90 (1955), published in Japan. * |
Katayama, "A Study on Prophylaxis for Recurrence of Bladder Tumor," 63(11):951-971 (1972), published in Japan. |
Katayama, A Study on Prophylaxis for Recurrence of Bladder Tumor, 63(11):951 971 (1972), published in Japan. * |
Kazuo et al., "Studies on Experimental Bladder Tumors. Report 3. Exzymologicl and Histological Study of the Effects of Both β-Glucuronidase Inhibitor and X-Ray Irradiation on Rat BBN Bladder Tumor," Chemical Abstracts, 86:361-362 (1977), Abstract No. 41460u, published in USA. |
Kazuo et al., Studies on Experimental Bladder Tumors. Report 3. Exzymologicl and Histological Study of the Effects of Both Glucuronidase Inhibitor and X Ray Irradiation on Rat BBN Bladder Tumor, Chemical Abstracts, 86:361 362 (1977), Abstract No. 41460u, published in USA. * |
Levvy, "The Preparation and Properties of β-Glucuronidase. 4. Inhibition by Sugar Acids and Their Lactones," Biochem., 52:464-472 (1952), published in USA. |
Levvy, The Preparation and Properties of Glucuronidase. 4. Inhibition by Sugar Acids and Their Lactones, Biochem., 52:464 472 (1952), published in USA. * |
Merck Index, p. 240, #1720 Candicidin, published in USA (1982). |
Merck Index, p. 240, 1720 Candicidin, published in USA (1982). * |
Miyakawa et al., "The Effect of Urinary β-Glucuronidase Inhibitor on the Induction of Bladder Tumors with 2-Acetylaminofluorene in Rats," Investigative Urology, 10(4):256-261 (1973), published in USA. |
Miyakawa et al., The Effect of Urinary Glucuronidase Inhibitor on the Induction of Bladder Tumors with 2 Acetylaminofluorene in Rats, Investigative Urology, 10(4):256 261 (1973), published in USA. * |
Product Information, Merck, Sharp & Dohme, 1413 (1989), published in USA. * |
Rawson et al., "Summation and Future Challenges," In: Inhibition of Tumor Induction and Development, Zedeck and Lipkin, editors, Plenum Press, New York, publishers, Chapter 9, pp. 219-223 (1981), published in USA. |
Rawson et al., Summation and Future Challenges, In: Inhibition of Tumor Induction and Development, Zedeck and Lipkin, editors, Plenum Press, New York, publishers, Chapter 9, pp. 219 223 (1981), published in USA. * |
Schneeman et al., "Similar Effects of Zinc Deficiency and Restricted Feeding on Plasma Lipids and Lipoproteins in Rats," J. Nutr., 116:1889-1895 (1986), published in USA. |
Schneeman et al., Similar Effects of Zinc Deficiency and Restricted Feeding on Plasma Lipids and Lipoproteins in Rats, J. Nutr., 116:1889 1895 (1986), published in USA. * |
Takada et al., "Effect of β-Glucuronidase Inhibitor on Azoxymethane-Induced Colonic Carcinogenesis in Rats," Cancer Research, 42:331-334 (1982), published in USA. |
Takada et al., Effect of Glucuronidase Inhibitor on Azoxymethane Induced Colonic Carcinogenesis in Rats, Cancer Research, 42:331 334 (1982), published in USA. * |
The Merck Manual of Diagnosis and Therapy, Fourteenth Edition, Robert Berkow, M.D., Editor in Chief, Merck Sharp & Dohme Research Laboratories, Publishers, Chapter 82, Anomalies in Lipid Metabolism, pp. 970 977(1982), published in USA. * |
The Merck Manual of Diagnosis and Therapy, Fourteenth Edition, Robert Berkow, M.D., Editor-in-Chief, Merck Sharp & Dohme Research Laboratories, Publishers, Chapter 82, "Anomalies in Lipid Metabolism," pp. 970-977(1982), published in USA. |
The United States Pharmacopeia, the National Formulary, Twenty First Revision (Jan. 1, 1985), p. 48, Calcium Gluconate, published in USA. * |
The United States Pharmacopeia, the National Formulary, Twenty-First Revision (Jan. 1, 1985), p. 48, Calcium Gluconate, published in USA. |
Walaszek et al., "Antiproliferative Effect of Dietary Glucarate on the Sprague-Dawley Rat Mammary Gland," Cancer Letters, 49:51-57, (1990), published in Ireland. |
Walaszek et al., "Antiproliferative Effects of Calcium D-Glucarate (CG) and D-Glucaro-1,4-Lactone (GL) on the Rat Mammary Gland, Colon and Mouse Skin," AACR Abstract Form (1990) printed in USA. |
Walaszek et al., "Effect of Calcium D-Glucarate on Development of the Rat Mammary Gland and Its Sensitivity to Chemical Carcinogenesis," and D-Glucarate Control of Intestinal Bacterial Microflora and Relationship to Cancer Prevention, Proceedings of the American Association for Cancer Research, 33:164 (1992), Abstract Nos. 981 and 982, published in USA. |
Walaszek et al., "Inhibition of 7,12-Dimethylbenzanthracene-Induced Rat Mammary Tumorigenesis by 2,5-DI-O-Acetyl-D-Glucaro-1,4:6,3-/Dilactone (Dagdl), an in Vivo β-Glucuronidase Inhibitor," Proceedings of the Seventh-Fifth Annual Meeting of the American Association for Cancer Research, May 9-12, (1984), 25:128, Abstract No. 507, published in Canada. |
Walaszek et al., "Inhibition of 7,12-Dimethylbenzanthracene-Induced Rat Mammary Tumorigenesis by 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone, an in vivo β-glucuronidase Inhibitor," carcinogenesis, 5(6):767-772 (1984), published in United Kingdom. |
Walaszek et al., Antiproliferative Effect of Dietary Glucarate on the Sprague Dawley Rat Mammary Gland, Cancer Letters, 49:51 57, (1990), published in Ireland. * |
Walaszek et al., Antiproliferative Effects of Calcium D Glucarate (CG) and D Glucaro 1,4 Lactone (GL) on the Rat Mammary Gland, Colon and Mouse Skin, AACR Abstract Form (1990) printed in USA. * |
Walaszek et al., Effect of Calcium D Glucarate on Development of the Rat Mammary Gland and Its Sensitivity to Chemical Carcinogenesis, and D Glucarate Control of Intestinal Bacterial Microflora and Relationship to Cancer Prevention, Proceedings of the American Association for Cancer Research, 33:164 (1992), Abstract Nos. 981 and 982, published in USA. * |
Walaszek et al., Inhibition of 7,12 Dimethylbenzanthracene Induced Rat Mammary Tumorigenesis by 2,5 DI O Acetyl D Glucaro 1,4:6,3 /Dilactone (Dagdl), an in Vivo Glucuronidase Inhibitor, Proceedings of the Seventh Fifth Annual Meeting of the American Association for Cancer Research, May 9 12, (1984), 25:128, Abstract No. 507, published in Canada. * |
Walaszek et al., Inhibition of 7,12 Dimethylbenzanthracene Induced Rat Mammary Tumorigenesis by 2,5 di O acetyl D glucaro 1,4:6,3 dilactone, an in vivo glucuronidase Inhibitor, carcinogenesis, 5(6):767 772 (1984), published in United Kingdom. * |
Willett et al., "Relation of Serum Vitamins A and E and Carotenoids to the Risk of Cancer," the New England Journal of Medicine, 310(7):430-434 (1984), published in USA. |
Willett et al., Relation of Serum Vitamins A and E and Carotenoids to the Risk of Cancer, the New England Journal of Medicine, 310(7):430 434 (1984), published in USA. * |
Cited By (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5561160A (en) * | 1990-05-16 | 1996-10-01 | Walaszek; Zbigniew | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders |
US5891459A (en) * | 1993-06-11 | 1999-04-06 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US20060009407A1 (en) * | 1993-06-11 | 2006-01-12 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US20040082659A1 (en) * | 1993-06-11 | 2004-04-29 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US6646006B2 (en) | 1993-06-11 | 2003-11-11 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US7452916B2 (en) | 1993-06-11 | 2008-11-18 | The Board Of Trustees Of The Leland Stanford Junior University | Enhancement of vascular function by modulation of endogenous nitric oxide production or activity |
US5626884A (en) * | 1995-08-18 | 1997-05-06 | Lockett; Curtis G. | Treatment of sickle cell disease |
WO1998050051A1 (en) * | 1995-08-18 | 1998-11-12 | Curtis Lockett | Treatment of sickle cell disease, treatment of immune system diseases and other diseases normally associated with sickle cell anemia |
US6069167A (en) * | 1996-01-16 | 2000-05-30 | University Technology Corporation | Use of antioxidant agents to treat cholestatic liver disease |
US6203818B1 (en) | 1997-03-20 | 2001-03-20 | Coventry Group, Ltd. | Nutritional supplement for cardiovascular health |
US6544563B2 (en) | 1998-04-03 | 2003-04-08 | The Daily Wellness Company | Method and composition for improving sexual fitness |
US7371415B1 (en) | 1998-04-03 | 2008-05-13 | The Daily Wellness Company | Method and composition for improving sexual fitness |
US20030203053A1 (en) * | 1998-04-03 | 2003-10-30 | Wuh Hank C.K. | Method and composition for improving sexual fitness |
US6368640B1 (en) | 1998-04-03 | 2002-04-09 | The Daily Wellness Company | Method and composition for improving sexual fitness |
US6103733A (en) * | 1998-09-09 | 2000-08-15 | Bachmann; Kenneth A. | Method for increasing HDL cholesterol levels using heteroaromatic phenylmethanes |
US20060159719A1 (en) * | 1999-06-05 | 2006-07-20 | The Board Of Trustees Of The Leland Stanford Junior University | Method and composition for inhibiting cardiovascular cell proliferation |
US20040074504A1 (en) * | 1999-06-05 | 2004-04-22 | Cooke John P. | Method and composition for inhibiting cardiovascular cell proliferation |
US20060167402A1 (en) * | 1999-06-05 | 2006-07-27 | The Board Of Trustees Of The Leland Stanford Junior University | Method and composition for inhibiting cardiovascular cell proliferation |
US20030026851A1 (en) * | 2000-12-22 | 2003-02-06 | Trant Aileen Sontag | Method and composition for improving fertility health in female and male animals and humans |
US6989164B2 (en) | 2000-12-22 | 2006-01-24 | The Daily Wellness Company | Method and composition for improving male fertility health |
US7045151B2 (en) | 2000-12-22 | 2006-05-16 | The Daily Wellness Company | Method and composition for improving fertility health in female and male animals and humans |
US6497885B2 (en) | 2000-12-22 | 2002-12-24 | The Daily Wellness Company | Method and composition for improving fertility health in female and male animals and humans |
US6596762B2 (en) | 2001-05-17 | 2003-07-22 | The Regents Of The University Of Colorado | Antioxidant compositions and use for treatment of hepatic steatosis and steatohepatitis |
US20070185203A1 (en) * | 2004-03-01 | 2007-08-09 | Rothbard Jonathan B | Compositions and Methods for Treating Diseases |
US7557087B2 (en) | 2004-03-01 | 2009-07-07 | Lumen Therapeutics, Llc | Compositions and methods for treating diseases |
US20050192210A1 (en) * | 2004-03-01 | 2005-09-01 | Rothbard Jonathan B. | Compositions and methods for treating diseases |
US8961813B2 (en) | 2006-08-07 | 2015-02-24 | The University Of Montana | Hydroxycarboxylic acids and salts |
US9162959B2 (en) | 2006-08-07 | 2015-10-20 | The University Of Montana | Method of oxidation using nitric acid |
US20090250653A1 (en) * | 2006-08-07 | 2009-10-08 | Kiely Donald E | Hydroxycarboxylic Acids and Salts |
US20100247505A1 (en) * | 2007-10-25 | 2010-09-30 | Nutri Co., Ltd. | Composition for Reducing the Level of Glucose, Malondialdehyde-Modified LDL, Homocysteine and/or C-Reactive Protein in Blood |
US10383893B2 (en) * | 2007-10-25 | 2019-08-20 | Nutri Co., Ltd. | Composition for reducing the level of glucose, malondialdehyde-modified LDL, homocysteine and/or C-reactive protein in blood |
US8623943B2 (en) | 2007-11-15 | 2014-01-07 | The University Of Montana | Hydroxypolyamide gel forming agents |
US20090131259A1 (en) * | 2007-11-15 | 2009-05-21 | Kiely Donald E | Hydroxypolyamide Gel Forming Agents |
US9315624B2 (en) | 2007-11-15 | 2016-04-19 | The University Of Montana | Hydroxypolyamide gel forming agents |
US9505882B2 (en) | 2007-11-15 | 2016-11-29 | The University Of Montana | Hydroxypolyamide gel forming agents |
US9404188B2 (en) | 2010-11-11 | 2016-08-02 | Rivertop Renewables | Corrosion inhibiting composition |
US9347024B2 (en) | 2011-04-21 | 2016-05-24 | Rivertop Renewables, Inc. | Calcium sequestering composition |
US9096787B2 (en) | 2012-11-28 | 2015-08-04 | Rivertop Renewables | Corrosion inhibiting, freezing point lowering compositions |
US9187398B2 (en) | 2013-03-13 | 2015-11-17 | Rivertop Renewables, Inc. | Nitric acid oxidation processes |
US9346736B2 (en) | 2013-03-13 | 2016-05-24 | Rivertop Renewables, Inc. | Oxidation process |
US9670124B2 (en) | 2013-03-13 | 2017-06-06 | Rivertop Renewables, Inc. | Nitric acid oxidation process |
US9758462B2 (en) | 2013-03-13 | 2017-09-12 | Rivertop Renewables, Inc. | Nitric acid oxidation processes |
Also Published As
Publication number | Publication date |
---|---|
US5561160A (en) | 1996-10-01 |
WO1991018593A1 (en) | 1991-12-12 |
EP0528950A1 (en) | 1993-03-03 |
EP0528950B1 (en) | 1996-09-11 |
EP0528950A4 (en) | 1993-03-24 |
JPH06504259A (en) | 1994-05-19 |
ATE142489T1 (en) | 1996-09-15 |
EP0730862A1 (en) | 1996-09-11 |
DE69122099D1 (en) | 1996-10-17 |
DE69122099T2 (en) | 1997-04-17 |
CA2080818A1 (en) | 1991-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5364644A (en) | Formula and method for the prevention and treatment of hypercholesterolemia and cellular hyperproliferative disorders | |
US6299896B1 (en) | Multi-vitamin and mineral supplement | |
US6228388B1 (en) | Multi-vitamin and mineral supplement for pregnant women | |
US7887847B2 (en) | Nutritional supplement for treatment of ocular diseases | |
US6953588B2 (en) | Multi-vitamin and mineral supplement | |
US8197854B2 (en) | Nutritional supplement for use under physiologically stressful conditions | |
WO1995035098A1 (en) | Multi-vitamin and mineral supplements for women | |
RU2663017C2 (en) | Nutritional supplements for 50+ individuals for improving vitality, immunity, eye and bone health | |
JP2004514684A (en) | Composition containing statin and calcium for improving cardiovascular health | |
US20060105033A1 (en) | Dietary composition containing conjugated linoleic acid and calcium for improved health | |
US20040166181A1 (en) | Compositions, methods, and kits for weight loss and inhibiting the loss of lean body mass | |
JPS58501676A (en) | Mixtures for supplying selenium to humans as a trace substance, as well as its use in media for cell culture, solutions for preserving organs and nutrient solutions for preserving blood components | |
EP0305097B1 (en) | Nutritional supplement | |
US6017946A (en) | Serotonin containing formulation for oral administration and method of use | |
US11596166B2 (en) | Compositions and methods for treating aging and/or improving human health | |
US20130064924A1 (en) | Nutritional supplement for use under physiologically stressful conditions | |
Kenny et al. | Clinical zinc deficiency during adequate enteral nutrition. | |
US7998500B2 (en) | Nutritional supplement for women | |
CN102578572A (en) | Mineral and vitamin nutritional supplement | |
WO2000007463A1 (en) | Multi-vitamin and mineral supplements for women | |
EP0432700A2 (en) | Use of lithium compounds for the treatment of combination skin | |
WO2003009840A1 (en) | Composition comprising at least one lipase inhibitor and carnitine | |
MXPA99000265A (en) | Dietetic supplements containing calcium citrate and carbonil iron |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM, Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WALASZEK, ZBIGNIEW;SLAGA, THOMAS J.;HANAUSEK, MARGARET;REEL/FRAME:006550/0493 Effective date: 19930225 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
CC | Certificate of correction | ||
AS | Assignment |
Owner name: WALASZEK, ZBIGNIEW, TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM;REEL/FRAME:007795/0969 Effective date: 19951229 Owner name: SLAGA, THOMAS J., TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM;REEL/FRAME:007795/0969 Effective date: 19951229 Owner name: HANAUSEK, MARGARET, TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:BOARD OF REGENTS, THE UNIVERSITY OF TEXAS SYSTEM;REEL/FRAME:007795/0969 Effective date: 19951229 |
|
FPAY | Fee payment |
Year of fee payment: 4 |
|
REMI | Maintenance fee reminder mailed | ||
FPAY | Fee payment |
Year of fee payment: 8 |
|
SULP | Surcharge for late payment |
Year of fee payment: 7 |
|
REMI | Maintenance fee reminder mailed | ||
FPAY | Fee payment |
Year of fee payment: 12 |
|
SULP | Surcharge for late payment |
Year of fee payment: 11 |